Six years ago, our UAB SPORE in Pancreatic Cancer application was partially funded via a P-20 grant. With limited funding;our mini-SPORE was composed of 2 major projects, 3 Cores and a Developmental Research Program. During this initial funding period, translation of SPORE science resulted in two phase I trials, one Phase II trial and a novel MRI imaging trial. The investigators of the SPORE have 88 publications relating to SPORE projects or pancreatic cancer. The Developmental Research funding resulted in two major projects, Projects 1, &4 in this renewal application and 2 awardees becoming Project co-leaders. Three years ago, Dr. Vickers (SPORE PI) became Chairman of Surgery at the University of Minnesota (UMN) and we restructured into a joint UAB/UMN SPORE in Pancreatic Cancer. The joint SPORE has functioned well and this proposal is our amended competitive renewal for full SPORE funding (PSO application). This proposal has 4 major projects: Project 1 is utilizing proteomic techniques in transgenic animal models to identify biomarkers that are predictive of early stage pancreatic cancer;Project 2 is a continuation project which is examining multiple methods to enhance the therapeutic efficacy of anti-DR5 monoclonal antibodies in pancreatic cancer animal models and patients;Project 3 is utilizing genomic and genetic data obtained from human pancreatic cancer (PCa) samples and observations from mouse models of PCa to understand the genetic events that drive metastasis and treatment resistance in this disease. These studies will lead to a phase I clinical trial;Project 4 is engineering novel conditionally replicative adenoviral vectors that target pancreatic cancer stem cell-like tumor cells for the treatment of metastatic pancreatic cancer. The four important and effective Cores are: 1) Administration;2) Tissue Resource and Molecular Pathology;3) Biostatistics;and 4) Clinical Management and Trials (Advocacy Sub-Core). We also request support for continuation of our Developmental Research and Career Development Programs which includes Morehouse School of Medicine and Tuskegee University. The application has strong institutional support from UAB and UMN, excellent pancreatic cancer populations and concurrence with federal guidelines.